OBJECTIVE Peritonitis is a major complication that arises out of peritoneal dialysis (PD), leading to death and loss of mesothelium and peritoneal injury, which may impede PD. We studied the combined impact of inflammatory mediators and PD fluids on mesothelial cell death. METHODS Cultured human mesothelial cells. RESULTS Inflammatory cytokines (TNF-α and interferon-γ) cooperate with bioincompatible PD fluids containing high glucose degradation product (GDP) concentrations to promote mesothelial cell death. Thus, the inflammatory cytokine cocktail induced a higher rate of death in cells cultured in high GDP PD fluid than in low GDP PD fluid or cell culture medium (cell death expressed as % hypodiploid cells: TNF-α and interferon-γ in RPMI: 14.15 ± 1.68, TNF-α and interferon-γ in 4.25% low GDP PD fluid 13.16 ± 3.29, TNF-α and interferon-γ in 4.25% high GDP PD fluid 25.88 ± 2.18%, p < 0.05 vs. the other two groups). BclxL BH4 peptides, Apaf-1 inhibition or caspase inhibition failed to protect from apoptosis induced by the combination of inflammatory cytokines and bioincompatible PD fluids, although they protected from other forms of mesothelial cell apoptosis. CONCLUSIONS Inflammation cooperates with high GDP PD fluids to promote mesothelial cell death, which is resistant to several therapeutic approaches. This information provides a framework for selection of PD fluid during peritonitis.